Target organ damage can ensue from several different primary triggers. One group of such primary triggers includes pathogenic autoantibodies that have affinity for glomerular antigens. Thus, it is clear that "nephrophilic" or "nephrotoxic" antibodies have the potential to target to the kidneys and compromise renal function. Currently, little is known about the genetic factors or the cellular players that determine the extent of target organ damage in immune nephritis. The long-term objective of this proposal is to shed light on these issues. This proposal aims to achieve this in several different ways. We have recently discovered that the 129/svJ strain demonstrates increased target organ damage when exposed to nephrophilic autoantibodies. In the first aim, we will identify the genetic loci that are responsible for the increased nephritis seen in 129/svJ mice. In the second aim, the impact of nephritis susceptibility loci on systemic immunity as well as renal disease will be studied. Finally, we will ascertain how nephritis susceptibility loci might impact the function of resident glomerulocytes in these mice. Collectively, these studies will deepen our understanding of the genetic factors and cellular elements leading to nephritis, particularly in systemic autoimmune diseases such as lupus. A better understanding of the genetic and cellular basis of target organ damage could potentially lead to more targeted therapies for nephritis in the future.